Eukaryotic organisms have an array of defense mechanisms to recognize, respond and control the numerous pathogens and harmful substances that they encounter every day. The Innate immune response is one of the first lines of defense to respond and defend in a non-specific manner. KSHV is a sexually transmitted agent in the USA and Western countries, and infects early during life in sub-Saharan Africa. In immune-suppressed individuals, KSHV is etiologically associated with inflammation associated malignancies such as Kaposi?s sarcoma (KS), primary effusion B-cell lymphoma (PEL), and Multicentric Castleman?s disease (MCD). Cytokines such as IL-1?, TNF-?, IFN-? and IL-6 as well as viral gene products are proposed to drive KS, PEL and MCD development and progression. KSHV infection of endothelial cells induces inflammatory cytokines and growth factors which are similar to the microenvironments of KS/PEL/MCD lesions. We hypothesize that constant activation of innate PRRs by KSHV could be one of the reasons for the chronic inflammation seen in KS, PEL and MCD lesions. Hence, our overall goals are to define the innate immune response against KSHV and to determine its role in KSHV?s biology. We have shown that the cytokine profiles elicited during de novo KSHV infection of human dermal microvascular endothelial cells are identical to the KS/PEL/MCD lesion microenvironments and pro- inflammatory IL-1? and IL-18 cytokines are secreted in the supernatants. IL-1? and IL-18 pro-forms undergo processing by activated caspase-1. Caspase-1, synthesized as procaspase-1, is auto-catalytically cleaved by the molecular platform ?inflammasome? that is formed by a sensor protein sensing the danger signal, adaptor molecule ASC and procaspase-1. Whether innate responses recognize and respond to the extra-chromosomal ds-circular KSHV genome (and other DNA viruses) in the nuclei were not known. Our studies for the first time demonstrated that IFI16, a highly conserved nuclear protein involved in transcription by unknown mechanism, is an innate nuclear sensor of KSHV, EBV and HSV-1 genomes. Follow up studies have revealed that IFI16 plays a role in latency maintenance of KSHV. Based on these studies we have extended our original hypothesis and hypothesize that IFI16 is in complex with different proteins in the nucleus to mediate different functions including innate sensing of episomal DNA and KSHV utilizes/subverts IFI16 and its associated proteins for its latency. Our exciting preliminary studies supports this hypothesis. To test this hypothesis, we have formulated two major focused and interlinked specific aims. These studies are significant since elucidating the role of IFI16 and its associated proteins in the nucleus in KSHV?s latency will allow a deeper understanding of its pathogenesis which will facilitate therapeutic manipulation of this pathway to control KSHV infection, inflammation and the associated malignancies.